Background: Difficulties in defining and characterizing phenotypes has hindered progress in psychiatric genetics and clinical neuroscience. Decreased approach-related behavior and anhedonia (lack of responsiveness to pleasure) are considered cardinal features of depression, but few studies have used laboratory-based measures to objectively characterize these constructs. Methods: To assess hedonic capacity in relation to depressive, particularly anhedonic, symptoms, 62 participants completed a signal-detection task based on a differential reinforcement schedule. Anhedonia was operationalized as decreased reward responsiveness. Results: Unequal frequency of reward between two correct responses produced a response bias (i.e., a systematic preference to identify the stimulus paired with the more frequent reward). Subjects with elevated depressive symptoms (Beck Depression Inventory scores ≥ 16) failed to show a response bias. Impaired reward responsiveness predicted higher anhedonic symptoms 1 month later, after controlling for general negative affectivity. Conclusions: Impaired tendency to modulate behavior as a function of prior reinforcement might underline diminished hedonic capacity in depression. When applied to a clinical population, objective assessments of participants’ propensity to modulate behavior as a function of reward might provide a powerful tool for improving the phenotypic definition of depression and thus offer a reliable behavioral screening approach for neuroscience studies of depression.